tbuckley/cabot-search huggingface dataset:
Neutralizing antibodies response to novel SARS-CoV-2 omicron sublineages in long-term care facility residents after the fourth dose of monovalent BNT162b2 COVID-19 vaccination
Authors: Ilenia Varasi, Alessia Lai, Lia Fiaschi, Annalisa Bergna, Antonella Gatti, Barbara Caimi, Camilla Biba, Carla Della Ventura, Claudia Balotta, Agostino Riva, Gianguglielmo Zehender, Maurizio Zazzi, Ilaria Vicenti
Journal: Journal of Infection (2023)
Role of Early Fluid Resuscitation in Pediatric Septic Shock
Authors: Joseph A. Carcillo
Journal: JAMA (1991)

<h3>Objective.</h3> —To examine the association of the volume of fluid administered at 1 and 6 hours after presentation, with survival and the occurrence of the adult respiratory distress syndrome, cardiogenic pulmonary edema, and persistent hypovolemia during the resuscitation of children with septic shock. <h3>Setting and Patients.</h3> —All pediatric patients with septic shock presenting to the emergency department over a 6-year period and having a pulmonary artery catheter inserted by 6 hours after presentation were identified. <h3>Methods.</h3> —Patients were analyzed together and in three groups based on fluid volume in the first hour: group 1, less than 20 mL/kg; group 2,20 to 40 mL/kg; and group 3, more than 40 mL/kg. Adult respiratory distress syndrome was diagnosed by the presence of alveolar infiltrates, hypoxemia, and a pulmonary capillary wedge pressure of 15 mm Hg or less. Cardiogenic pulmonary edema was diagnosed similarly, except the pulmonary capillary wedge pressure was greater than 15 mm Hg. Hypovolemia was diagnosed by the presence of oliguria, hypotension, and a pulmonary capillary wedge pressure of 8 mm Hg or less 6 hours after presentation. <h3>Results.</h3> —We identified 34 patients (median age, 13.5 months). At 1 and 6 hours, respectively, group 1 (n = 14) received 11 ±6 and 71 ±29 mL/kg (mean ± SD) of fluid; group 2 received 32 ±5 and 108 ±54 mL/kg of fluid; and group 3 received 69 ± 19 and 117 ± 29 mL/kg of fluid. Survival in group 3 (eight of nine patients) was significantly better than in group 1 (six of 14 patients) or group 2 (four of 11 patients). Adult respiratory distress syndrome developed in 11 patients (32%) and cardiogenic pulmonary edema developed in five patients (15%). Having adult respiratory distress syndrome was associated with increased mortality, but adult respiratory distress syndrome was not increased in any group. Similarly, cardiogenic pulmonary edema was not associated with the fluid volume received or with decreased survival. Hypovolemia occurred in six patients in group 1 and two patients in group 2; all eight subsequently died. <h3>Conclusion.</h3> —Rapid fluid resuscitation in excess of 40 mL/kg in the first hour following emergency department presentation was associated with improved survival, decreased occurrence of persistent hypovolemia, and no increase in the risk of cardiogenic pulmonary edema or adult respiratory distress syndrome in this group of Pediatric patients with septic shock. (<i>JAMA</i>. 1991;266:1242-1245)
Fancm has dual roles in the limiting of meiotic crossovers and germ cell maintenance in mammals
Authors: Vanessa Tsui, Ruqian Lyu, Stevan Novakovic, Jessica M. Stringer, Jessica E.M. Dunleavy, Elissah Granger, Tim Semple, Anna Leichter, Luciano G. Martelotto, D. Jo Merriner, Ruijie Liu, Lucy McNeill, Nadeen Zerafa, Eva R. Hoffmann, Moira K. O’Bryan, Karla Hutt, Andrew J. Deans, Jörg Heierhorst, Davis J. McCarthy, Wayne Crismani
Journal: Cell Genomics (2023)

Meiotic crossovers are required for accurate chromosome segregation and producing new allelic combinations. Meiotic crossover numbers are tightly regulated within a narrow range, despite an excess of initiating DNA double-strand breaks. Here, we reveal the tumor suppressor FANCM as a meiotic anti-crossover factor in mammals. We use unique large-scale crossover analyses with both single-gamete sequencing and pedigree-based bulk-sequencing datasets to identify a genome-wide increase in crossover frequencies in Fancm-deficient mice. Gametogenesis is heavily perturbed in Fancm loss-of-function mice, which is consistent with the reproductive defects reported in humans with biallelic FANCM mutations. A portion of the gametogenesis defects can be attributed to the cGAS-STING pathway after birth. Despite the gametogenesis phenotypes in Fancm mutants, both sexes are capable of producing offspring. We propose that the anti-crossover function and role in gametogenesis of Fancm are separable and will inform diagnostic pathways for human genomic instability disorders.
Blood transcriptional correlates of BCG-induced protection against tuberculosis in rhesus macaques
Authors: Yiran E. Liu, Patricia A. Darrah, Joseph J. Zeppa, Megha Kamath, Farida Laboune, Daniel C. Douek, Pauline Maiello, Mario Roederer, JoAnne L. Flynn, Robert A. Seder, Purvesh Khatri
Journal: Cell Reports Medicine (2023)

Blood-based correlates of vaccine-induced protection against tuberculosis (TB) are urgently needed. Here, we analyze the blood transcriptome of rhesus macaques immunized with varying doses of intravenous (i.v.) BCG followed by Mycobacterium tuberculosis (Mtb) challenge. We use high-dose i.v. BCG recipients for "discovery" and validate our findings in low-dose recipients and in an independent cohort of macaques receiving BCG via different routes. We identify seven vaccine-induced gene modules, including an innate module (module 1) enriched for type 1 interferon and RIG-I-like receptor signaling pathways. Module 1 on day 2 post-vaccination highly correlates with lung antigen-responsive CD4 T cells at week 8 and with Mtb and granuloma burden following challenge. Parsimonious signatures within module 1 at day 2 post-vaccination predict protection following challenge with area under the receiver operating characteristic curve (AUROC) ≥0.91. Together, these results indicate that the early innate transcriptional response to i.v. BCG in peripheral blood may provide a robust correlate of protection against TB.
Caspase-8 inhibition improves the outcome of bacterial infections in mice by promoting neutrophil activation
Authors: Germana Lentini, Agata Famà, Giuseppe Valerio De Gaetano, Francesco Coppolino, Ahlem Khachroub Mahjoub, Liv Ryan, Egil Lien, Terje Espevik, Concetta Beninati, Giuseppe Teti
Journal: Cell Reports Medicine (2023)

During differentiation, neutrophils undergo a spontaneous pro-inflammatory program that is hypothesized here to be under caspase-8 control. In mice, intraperitoneal administration of the caspase-8 inhibitor z-IETD-fmk is sufficient to unleash the production of pro-inflammatory cytokines and neutrophil influx in the absence of cell death. These effects are due to selective inhibition of caspase-8 and require tonic interferon-β (IFN-β) production and RIPK3 but not MLKL, the essential downstream executioner of necroptotic cell death. In vitro, stimulation with z-IETD-fmk is sufficient to induce significant cytokine production in murine neutrophils but not in macrophages. Therapeutic administration of z-IETD-fmk improves clinical outcome in models of lethal bacterial peritonitis and pneumonia by augmenting cytokine release, neutrophil influx, and bacterial clearance. Moreover, the inhibitor protects mice against high-dose endotoxin shock. Collectively, our data unveil a RIPK3- and IFN-β-dependent pathway that is constitutively activated in neutrophils and can be harnessed therapeutically using caspase-8 inhibition.
Genomic Alterations and the Incidence of Brain Metastases in Advanced and Metastatic NSCLC: A Systematic Review and Meta-Analysis
Authors: Conor S. Gillespie, Mohammad A. Mustafa, George E. Richardson, Ali M. Alam, Keng Siang Lee, David M. Hughes, Carles Escriu, Rasheed Zakaria
Journal: Journal of Thoracic Oncology (2023)
Plasma protein biomarkers predict the development of persistent autoantibodies and type 1 diabetes 6 months prior to the onset of autoimmunity
Authors: Ernesto S. Nakayasu, Lisa M. Bramer, Charles Ansong, Athena A. Schepmoes, Thomas L. Fillmore, Marina A. Gritsenko, Therese R. Clauss, Yuqian Gao, Paul D. Piehowski, Bryan A. Stanfill, Dave W. Engel, Daniel J. Orton, Ronald J. Moore, Wei-Jun Qian, Salvatore Sechi, Brigitte I. Frohnert, Jorma Toppari, Anette-G. Ziegler, Åke Lernmark, William Hagopian, Beena Akolkar, Richard D. Smith, Marian J. Rewers, Bobbie-Jo M. Webb-Robertson, Thomas O. Metz
Journal: Cell Reports Medicine (2023)

Type 1 diabetes (T1D) results from autoimmune destruction of β cells. Insufficient availability of biomarkers represents a significant gap in understanding the disease cause and progression. We conduct blinded, two-phase case-control plasma proteomics on the TEDDY study to identify biomarkers predictive of T1D development. Untargeted proteomics of 2,252 samples from 184 individuals identify 376 regulated proteins, showing alteration of complement, inflammatory signaling, and metabolic proteins even prior to autoimmunity onset. Extracellular matrix and antigen presentation proteins are differentially regulated in individuals who progress to T1D vs. those that remain in autoimmunity. Targeted proteomics measurements of 167 proteins in 6,426 samples from 990 individuals validate 83 biomarkers. A machine learning analysis predicts if individuals would remain in autoimmunity or develop T1D 6 months before autoantibody appearance, with areas under receiver operating characteristic curves of 0.871 and 0.918, respectively. Our study identifies and validates biomarkers, highlighting pathways affected during T1D development.
MASS SPECTROMETRY AS A TOOL FOR MINIMAL RESIDUAL DISEASE DETECTION IN THE BLOOD OF MYELOMA PATIENTS
Authors: J.F.M. Jacobs
Journal: HemaSphere (2023)

M-protein detection and quantification are integral parts of the diagnosis and monitoring of multiple myeloma. Novel treatment modalities impose new challenges on the traditional electrophoretic and immunochemical methods that are routinely used for M-protein diagnostics, most importantly the need for increased sensitivity to measure minimal residual disease (MRD). In the past two decades flow cytometric and next generation sequencing methods have been developed to assess MRD in bone marrow aspirates of patients with multiple myeloma. MRD-status is an important independent prognostic marker and its potential as surrogate endpoint for progression-free survival is currently studied. In addition to that, numerous clinical trials are investigating the added clinical value of MRD-guided therapy decisions in individual patients. Because of these novel clinical applications, repeated MRD-evaluation is becoming common practice, also in regular management of patients outside clinical trials. A disadvantage of MRD-evaluation on bone marrow aspirates is the risk of sampling-error, resulting from heterogenous dispersion of myeloma cells and/or extramedullary myeloma outgrowth. In addition, invasive bone marrow biopsies are a burden to patients. Recently, advances have been made in ultra-sensitive detection and quantitation of serum M-proteins using mass spectrometry (MS-MRD), which represents an attractive minimally invasive alternative to bone marrow-based MRD-evaluation. Several studies have shown that MS-MRD blood-testing is feasible in all patients with multiple myeloma and that it has similar sensitivity and prognostic value compared to NGS-MRD evaluation performed on bone marrow. The MS-MRD blood-test paves the way for dynamic MRD monitoring to allow detection of early disease relapse (see Figure) and may proof to be a crucial factor to facilitate future clinical implementation of MRD-guided therapy.Figure.: Early relapse detection with dynamic MS-MRD monitoring.MS-MRD blood monitoring on 26 sera of one patient with multiple myeloma treated in the IFM2009 clinical trial. The increased sensitivity of MS-MRD (black) compared to routine M-protein diagnostics (blue) allows early detection of disease relapse.
Deep-penetration functionalized cuttlefish ink nanoparticles for combating wound infections with synergetic photothermal-immunologic therapy
Authors: Wen-Qiang Qu, Jin-Xuan Fan, Di-Wei Zheng, Hui-Yun Gu, Yi-Feng Yu, Xiao Yan, Kai Zhao, Zhong-Bao Hu, Bai-Wen Qi, Xian-Zheng Zhang, Ai-Xi Yu
Journal: Biomaterials (2023)
Leveraging immune resistance archetypes in solid cancer to inform next-generation anticancer therapies
Authors: Kristin G Anderson, David A Braun, Aitziber Buqué, Sarah B Gitto, Jennifer L Guerriero, Brendan Horton, Bridget P Keenan, Teresa S Kim, Abigail Overacre-Delgoffe, Marco Ruella, Todd A Triplett, Omkara Veeranki, Vivek Verma, Fan Zhang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Anticancer immunotherapies, such as immune checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T cells, have improved outcomes for patients with a variety of malignancies. However, most patients either do not initially respond or do not exhibit durable responses due to primary or adaptive/acquired immune resistance mechanisms of the tumor microenvironment. These suppressive programs are myriad, different between patients with ostensibly the same cancer type, and can harness multiple cell types to reinforce their stability. Consequently, the overall benefit of monotherapies remains limited. Cutting-edge technologies now allow for extensive tumor profiling, which can be used to define tumor cell intrinsic and extrinsic pathways of primary and/or acquired immune resistance, herein referred to as features or feature sets of immune resistance to current therapies. We propose that cancers can be characterized by immune resistance archetypes, comprised of five feature sets encompassing known immune resistance mechanisms. Archetypes of resistance may inform new therapeutic strategies that concurrently address multiple cell axes and/or suppressive mechanisms, and clinicians may consequently be able to prioritize targeted therapy combinations for individual patients to improve overall efficacy and outcomes.
Resolving therapy resistance mechanisms in multiple myeloma by multiomics subclone analysis
Authors: Alexandra M. Poos, Nina Prokoph, Moritz J. Przybilla, Jan-Philipp Mallm, Simon Steiger, Isabelle Seufert, Lukas John, Stephan M. Tirier, Katharina Bauer, Anja Baumann, Jennifer Rohleder, Umair Munawar, Leo Rasche, K. Martin Kortüm, Nicola Giesen, Philipp Reichert, Stefanie Huhn, Carsten Müller-Tidow, Hartmut Goldschmidt, Oliver Stegle, Marc S. Raab, Karsten Rippe, Niels Weinhold
Journal: Blood (2023)

Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this challenge, the characterization of resistance mechanisms at the subclonal level is key to identify common vulnerabilities. In this study, we integrate whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and chromatin accessibility (scATAC sequencing) together with mitochondrial DNA mutations to define subclonal architecture and evolution for longitudinal samples from 15 patients with relapsed or refractory multiple myeloma. We assess transcriptomic and epigenomic changes to resolve the multifactorial nature of therapy resistance and relate it to the parallel occurrence of different mechanisms: (1) preexisting epigenetic profiles of subclones associated with survival advantages, (2) converging phenotypic adaptation of genetically distinct subclones, and (3) subclone-specific interactions of myeloma and bone marrow microenvironment cells. Our study showcases how an integrative multiomics analysis can be applied to track and characterize distinct multidrug-resistant subclones over time for the identification of molecular targets against them.
Limited efficacy of APRIL CAR in patients with multiple myeloma indicate challenges in the use of natural ligands for CAR T-cell therapy
Authors: Lydia Lee, Wen Chean Lim, Daria Galas-Filipowicz, Kent Fung, Julia Taylor, Dominic Patel, Zulaikha Akbar, Elena Alvarez Mediavilla, Patrycja Wawrzyniecka, Debarati Shome, Rogier M Reijmers, Trillian Gregg, Leigh Wood, William Day, Virginie Cerec, Mathieu Ferrari, Simon Thomas, Shaun Cordoba, Shimobi Onuoha, Nushmia Khokhar, Vijay Peddareddigari, Muhammad Al-Hajj, Jim Cavet, Sonja Zweegman, Manuel Rodriguez-Justo, Kwee Yong, Martin Pule, Rakesh Popat
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background We used a proliferating ligand (APRIL) to construct a ligand-based third generation chimeric antigen receptor (CAR) able to target two myeloma antigens, B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor. Methods The APRIL CAR was evaluated in a Phase 1 clinical trial ( NCT03287804 , AUTO2) in patients with relapsed, refractory multiple myeloma. Eleven patients received 13 doses, the first 15×10 6 CARs, and subsequent patients received 75,225,600 and 900×10 6 CARs in a 3+3 escalation design. Results The APRIL CAR was well tolerated. Five (45.5%) patients developed Grade 1 cytokine release syndrome and there was no neurotoxicity. However, responses were only observed in 45.5% patients (1×very good partial response, 3×partial response, 1×minimal response). Exploring the mechanistic basis for poor responses, we then compared the APRIL CAR to two other BCMA CARs in a series of in vitro assays, observing reduced interleukin-2 secretion and lack of sustained tumor control by APRIL CAR regardless of transduction method or co-stimulatory domain. There was also impaired interferon signaling of APRIL CAR and no evidence of autoactivation. Thus focusing on APRIL itself, we confirmed similar affinity to BCMA and protein stability in comparison to BCMA CAR binders but reduced binding by cell-expressed APRIL to soluble BCMA and reduced avidity to tumor cells. This indicated either suboptimal folding or stability of membrane-bound APRIL attenuating CAR activation. Conclusions The APRIL CAR was well tolerated, but the clinical responses observed in AUTO2 were disappointing. Subsequently, when comparing the APRIL CAR to other BCMA CARs, we observed in vitro functional deficiencies due to reduced target binding by cell-expressed ligand.
Obinutuzumab Versus Rituximab Immunochemotherapy in Previously Untreated iNHL: Final Results From the GALLIUM Study
Authors: William Townsend, Wolfgang Hiddemann, Christian Buske, Guillaume Cartron, David Cunningham, Martin J.S. Dyer, John G. Gribben, Elizabeth H. Phillips, Martin Dreyling, John F. Seymour, Andrew Grigg, Judith Trotman, Tong-Yu Lin, Xiao-Nan Hong, Dirk Kingbiel, Tina G. Nielsen, Andrea Knapp, Michael Herold, Robert Marcus
Journal: HemaSphere (2023)

The phase III GALLIUM trial assessed the safety and efficacy of obinutuzumab-based versus rituximab-based immunochemotherapy in patients with previously untreated follicular lymphoma (FL) or marginal zone lymphoma (MZL). At the primary analysis, the trial met its primary end point, demonstrating improvement in investigator-assessed progression-free survival (PFS) with obinutuzumab-based versus rituximab-based immunochemotherapy in patients with FL. We report the results of the final analysis in the FL population, with an additional exploratory analysis in the MZL subgroup. Overall, 1202 patients with FL were randomized 1:1 to obinutuzumab- or rituximab-based immunochemotherapy followed by maintenance with the same antibody for up to 2 years. After a median 7.9 (range, 0.0-9.8) years of follow-up, PFS remained improved with obinutuzumab- versus rituximab-based immunochemotherapy, with 7-year PFS rates of 63.4% versus 55.7% (P = 0.006). Time-to-next antilymphoma treatment was also improved (74.1% versus 65.4% of patients had not started their next antilymphoma treatment at 7 y; P = 0.001). Overall survival was similar between the arms (88.5% versus 87.2%; P = 0.36). Irrespective of the treatment received, PFS and OS were higher in patients with a complete molecular response (CMR) versus those with no CMR (P < 0.001). Serious adverse events were reported in 48.9% and 43.4% of patients in the obinutuzumab and rituximab arms, respectively; there was no difference in the rate of fatal adverse events (4.4% and 4.5%, respectively). No new safety signals were reported. These data demonstrate the long-term benefit of obinutuzumab-based immunochemotherapy and confirm its role as a standard-of-care for the first-line treatment of advanced-stage FL, taking into account patient characteristics and safety considerations.
Association between gene expression signatures and clinical outcomes of pembrolizumab versus paclitaxel in advanced gastric cancer: exploratory analysis from the randomized, controlled, phase III KEYNOTE-061 trial
Authors: Kohei Shitara, Maria Di Bartolomeo, Mario Mandala, Min-Hee Ryu, Christian Caglevic, Tomasz Olesinski, Hyun Cheol Chung, Kei Muro, Eray Goekkurt, Raymond S McDermott, Wasat Mansoor, Zev A Wainberg, Chie-Schin Shih, Julie Kobie, Michael Nebozhyn, Razvan Cristescu, Z Alexander Cao, Andrey Loboda, Mustafa Özgüroğlu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background In the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1-positive (combined positive score ≥1) advanced gastric/gastroesophageal junction (G/GEJ) cancer but did elicit a longer duration of response and offered a favorable safety profile. This prespecified exploratory analysis was conducted to evaluate associations between tumor gene expression signatures and clinical outcomes in the phase III KEYNOTE-061 trial. Methods Using RNA sequencing data obtained from formalin-fixed, paraffin-embedded baseline tumor tissue samples, we evaluated the 18-gene T-cell-inflamed gene expression profile (Tcell inf GEP) and 10 non-Tcell inf GEP signatures (angiogenesis, glycolysis, granulocytic myeloid-derived suppressor cell (gMDSC), hypoxia, monocytic MDSC (mMDSC), MYC, proliferation, RAS, stroma/epithelial-to-mesenchymal transition/transforming growth factor-β, WNT). The association between each signature on a continuous scale and outcomes was analyzed using logistic (objective response rate (ORR)) and Cox proportional hazards regression (progression-free survival (PFS) and OS). One-sided (pembrolizumab) and two-sided (paclitaxel) p values were calculated for Tcell inf GEP (prespecified α=0.05) and the 10 non-Tcell inf GEP signatures (multiplicity-adjusted; prespecified α=0.10). Results RNA sequencing data were available for 137 patients in each treatment group. Tcell inf GEP was positively associated with ORR (p=0.041) and PFS (p=0.026) for pembrolizumab but not paclitaxel (p&gt;0.05). The Tcell inf GEP-adjusted mMDSC signature was negatively associated with ORR (p=0.077), PFS (p=0.057), and OS (p=0.033) for pembrolizumab, while the Tcell inf GEP-adjusted glycolysis (p=0.018), MYC (p=0.057), and proliferation (p=0.002) signatures were negatively associated with OS for paclitaxel. Conclusions This exploratory analysis of tumor Tcell inf GEP showed associations with ORR and PFS for pembrolizumab but not for paclitaxel. Tcell inf GEP-adjusted mMDSC signature was negatively associated with ORR, PFS, and OS for pembrolizumab but not paclitaxel. These data suggest myeloid-driven suppression may play a role in resistance to PD-1 inhibition in G/GEJ cancer and support a strategy of considering immunotherapy combinations which target this myeloid axis. Trial registration number NCT02370498 .